In a prospective, randomized trial involving patients with resected pancreatic cancer, adjuvant combination chemotherapy with FOLFIRINOX resulted in a median disease-free survival of 21.6 months, as ...compared with 12.8 months with gemcitabine therapy. Overall survival was also longer with FOLFIRINOX.
Pancreatic carcinoma is one of the leading causes of cancer-related mortality. At the time of diagnosis, 30% of patients present with a locally advanced pancreatic carcinoma (LAPC). As circulating ...tumor cells (CTCs) count may be a surrogate of the cancer metastatic abilities, CTC detection rates and prognostic value were studied in a prospective cohort of LAPC patients.
An LAP07 international multicenter randomized study assesses in patients whose LAPC is controlled after 4 months of chemotherapy whether chemoradiotherapy could increase survival versus continuation of chemotherapy. A subgroup of patients included in the LAP07 trial was screened for CTCs (CellSearch®) before the start of the chemotherapy and after 2 months of treatment. Patient characteristics and survival were obtained prospectively and were correlated with CTC detection.
Seventy-nine patients were included. One or more CTCs/7.5 ml were detected in 5% of patients before treatment and in 9% of patients after 2 months of treatment (overall detection rate: 11% of patients). CTC positivity was associated with poor tumor differentiation (P = 0.04), and with shorter overall survival (OS) in multivariable analysis (RR = 2.5, P = 0.01), together with anemia.
The evaluation of micrometastatic disease using CTC detection appears as a promising prognostic tool in LAPC patients.
Background
BRAF mutation is associated with a poor prognosis in patients with metastatic colorectal cancer. For patients with resectable colorectal liver metastases (CRLMs), the prognostic impact of ...BRAF mutation is unknown and the benefit of surgery debated. This nationwide intergroup (ACHBT, FRENCH, AGEO) study aimed to evaluate the oncological outcome of patients undergoing liver resection for BRAF‐mutated CRLMs.
Methods
The study included patients who underwent resection for BRAF‐mutated CRLMs in 24 centres between 2012 and 2016. A case‐matched comparison was made with 183 patients who underwent resection of CRLMs with wild‐type BRAF during the same interval.
Results
Sixty‐six patients who underwent resection for BRAF‐mutated CRLMs in 24 centres were compared with 183 patients with wild‐type BRAF. The 1‐ and 3‐year disease‐free survival (DFS) rates were 46 and 19 per cent for the BRAF‐mutated group, and 55·4 and 27·8 per cent for the group with wild‐type BRAF (P = 0·430). In multivariable analysis, BRAF mutation was not associated with worse DFS (hazard ratio 1·16, 95 per cent c.i. 0·72 to 1·85; P = 0·547). The 1‐ and 3‐year overall survival rates after surgery were 94 and 54 per cent respectively among patients with BRAF mutation, and 95·8 and 82·9 per cent in those with wild‐type BRAF (P = 0·004). Median survival after disease progression was 23·0 (95 per cent c.i. 11·0 to 35·0) months among patients with mutated BRAF and 44·3 (35·9 to 52·6) months in those with wild‐type BRAF (P = 0·050). Multisite disease progression was more common in the BRAF‐mutated group (48 versus 29·8 per cent; P = 0·034).
Conclusion
These results support surgical treatment for resectable BRAF‐mutated CRLM, as BRAF mutation by itself does not increase the risk of relapse after resection. BRAF mutation is associated with worse survival in patients whose disease relapses after resection of CRLM, as for non‐metastatic colorectal cancer.
For patients with resectable colorectal liver metastases, the prognostic impact of BRAF mutation is unknown and the benefit of surgery debated. This nationwide case–control study showed that BRAF mutation by itself does not increase the risk of relapse after surgery, but is associated with worse survival after relapse. wtBRAF, wild‐type BRAF; mutBRAF, mutated BRAF.
No effect on recurrence
RAS mutations are currently sought for in tumor samples, which takes a median of almost 3weeks in western European countries. This creates problems in clinical situations that require urgent ...treatment and for inclusion in therapeutic trials that need RAS status for randomization. Analysis of circulating tumor DNA might help to shorten the time required to determine RAS mutational status before anti-epidermal growth factor receptor antibody therapy for metastatic colorectal cancer. Here we compared plasma with tissue RAS analysis in a large prospective multicenter cohort.
Plasma samples were collected prospectively from chemotherapy-naive patients and analyzed centrally by next-generation sequencing (NGS) with the colon lung cancer V2 Ampliseq panel and by methylation digital PCR (WIF1 and NPY genes). Tumoral RAS status was determined locally, in parallel, according to routine practice. For a minimal κ coefficient of 0.7, reflecting acceptable concordance (precision±0.07), with an estimated 5% of non-exploitable data, 425 subjects were necessary.
From July 2015 to December 2016, 425 patients were enrolled. For the 412 patients with available paired plasma and tumor samples, the κ coefficient was 0.71 95% confidence interval (CI), 0.64–0.77 and accuracy was 85.2% (95% CI, 81.4% to 88.5%). In the 329 patients with detectable ctDNA (at least one mutation or one methylated biomarker), the κ coefficient was 0.89 (95% CI, 0.84–0.94) and accuracy was 94.8% (95% CI, 91.9% to 97.0%). The absence of liver metastases was the main clinical factor associated with inconclusive circulating tumor DNA results odds ratio=0.11 (95% CI, 0.06–0.21). In patients with liver metastases, accuracy was 93.5% with NGS alone and 97% with NGS plus the methylated biomarkers.
This prospective trial demonstrates excellent concordance between RAS status in plasma and tumor tissue from patients with colorectal cancer and liver metastases, thus validating plasma testing for routine RAS mutation analysis in these patients.
Clinicaltrials.gov, NCT02502656.
Patients treated with chemotherapy for microsatellite unstable (MSI) and/or mismatch repair deficient (dMMR) cancer metastatic colorectal cancer (mCRC) exhibit poor prognosis. We aimed to evaluate ...the relevance of distinguishing sporadic from Lynch syndrome (LS)-like mCRCs.
MSI/dMMR mCRC patients were retrospectively identified in six French hospitals. Tumour samples were screened for MSI, dMMR, RAS/RAF mutations and MLH1 methylation. Sporadic cases were molecularly defined as those displaying MLH1/PMS2 loss of expression with BRAFV600E and/or MLH1 hypermethylation and no MMR germline mutation.
Among 129 MSI/dMMR mCRC patients, 81 (63%) were LS-like and 48 (37%) had sporadic tumours; 22% of MLH1/PMS2-negative mCRCs would have been misclassified using an algorithm based on local medical records (age, Amsterdam II criteria, BRAF and MMR statuses when locally tested), compared to a systematical assessment of MMR, BRAF and MLH1 methylation statuses. In univariate analysis, parameters associated with better overall survival were age (P < 0.0001), metastatic resection (P = 0.001) and LS-like mCRC (P = 0.01), but not BRAFV600E. In multivariate analysis, age (hazard ratio (HR) = 3.19, P = 0.01) and metastatic resection (HR = 4.2, P = 0.001) were associated with overall survival, but not LS. LS-like patients were associated with more frequent liver involvement, metastatic resection and better disease-free survival after metastasectomy (HR = 0.28, P = 0.01). Median progression-free survival of first-line chemotherapy was similar between the two groups (4.2 and 4.2 months; P = 0.44).
LS-like and sporadic MSI/dMMR mCRCs display distinct natural histories. MMR, BRAF mutation and MLH1 methylation testing should be mandatory to differentiate LS-like and sporadic MSI/dMMR mCRC, to determine in particular whether immune checkpoint inhibitors efficacy differs in these two populations.
•Metastatic colorectal cancers with sporadic or inherited MMR deficiency display distinct natural histories.•A algorithm combining MMR protein expression, BRAF mutation and MLH1 methylation is mandatory to properly determine the mechanism of MMR deficiency.•A better characterisation of dMMR CRCs is needed to determine whether therapeutic agents efficacy differs depending on the origin of the MMR deficiency.
Chemotherapy is the only systemic treatment approved for pancreatic ductal adenocarcinoma (PDAC), with a selection of regimens based on patients' performance status and expected efficacy. The ...establishment of a potent stratification associated with chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments.
Concomitant chemosensitivity and genome-wide RNA profiles were carried out on preclinical models (primary cell cultures and patient-derived xenografts) derived from patients with PDAC included in the PaCaOmics program (NCT01692873). The RNA-based stratification was tested in a monocentric cohort and validated in a multicentric cohort, both retrospectively collected from resected PDAC samples (67 and 368 patients, respectively). Forty-three (65%) and 203 (55%) patients received adjuvant gemcitabine in the monocentric and the multicentric cohorts, respectively. The relationships between predicted gemcitabine sensitivity and patients' overall survival (OS) and disease-free survival were investigated.
The GemPred RNA signature was derived from preclinical models, defining gemcitabine sensitive PDAC as GemPred+. Among the patients who received gemcitabine in the test and validation cohorts, the GemPred+ patients had a higher OS than GemPred− (P = 0.046 and P = 0.00216). In both cohorts, the GemPred stratification was not associated with OS among patients who did not receive gemcitabine. Among gemcitabine-treated patients, GemPred+ patients had significantly higher OS than the GemPred−: 91.3 months 95% confidence interval (CI): 61.2-not reached versus 33 months (95% CI: 24-35.2); hazard ratio 0.403 (95% CI: 0.221-0.735, P = 0.00216). The interaction test for gemcitabine and GemPred+ stratification was significant (P = 0.0245). Multivariate analysis in the gemcitabine-treated population retained an independent predictive value.
The RNA-based GemPred stratification predicts the benefit of adjuvant gemcitabine in PDAC patients.
•An RNA signature of gemcitabine-sensitivity is developed from in vitro and in vivo models of pancreatic cancer.•The resulting GemPred signature identifies a subgroup of patients who are sensitive to adjuvant gemcitabine.•The predictive value of GemPred is validated in two cohorts on both OS and disease-free survival.
First-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) includes nab-paclitaxel/gemcitabine. Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumor activity through ...tumor microenvironment modulation. The safety and efficacy of first-line ibrutinib plus nab-paclitaxel/gemcitabine treatment in patients with PDAC were evaluated.
RESOLVE (NCT02436668) was a phase III, randomized, double-blind, placebo-controlled study. Patients (histologically-confirmed PDAC; stage IV diagnosis ≥6 weeks of randomization; Karnofsky performance score ≥70) were randomized to once-daily oral ibrutinib (560 mg) or placebo plus nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2). Primary endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS); overall response rate and safety were assessed.
In total, 424 patients were randomized (ibrutinib arm, n = 211; placebo arm, n = 213). Baseline characteristics were balanced across arms. After a median follow-up of 25 months, there was no significant difference in OS between ibrutinib plus nab-paclitaxel/gemcitabine versus placebo plus nab-paclitaxel/gemcitabine (median of 9.7 versus 10.8 months; P = 0.3225). PFS was shorter for ibrutinib plus nab-paclitaxel/gemcitabine compared with placebo plus nab-paclitaxel/gemcitabine (median 5.3 versus 6.0 months; P < 0.0001). Overall response rates were 29% and 42%, respectively (P = 0.0058). Patients in the ibrutinib arm had less time on treatment and received lower cumulative doses for all agents compared with the placebo arm. The most common grade ≥3 adverse events for ibrutinib versus placebo arms included neutropenia (24% versus 35%), peripheral sensory neuropathy (17% versus 8%), and anemia (16% versus 17%). Primary reasons for any treatment discontinuation were disease progression and adverse events.
Ibrutinib plus nab-paclitaxel/gemcitabine did not improve OS or PFS for patients with PDAC. Safety was consistent with known profiles for these agents.
•Addition of ibrutinib to nab-paclitaxel/gemcitabine did not improve efficacy outcomes for pancreatic ductal adenocarcinoma.•Primary endpoints—overall survival and investigator-assessed progression-free survival—were not met in this phase III study.•Ibrutinib treatment led to less time on treatment and lower cumulative dose for all agents compared with placebo treatment.•Reported safety was consistent with the known profiles for ibrutinib and nab-paclitaxel/gemcitabine.
The purpose of this study was to evaluate the combination of panitumumab and irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy (oxaliplatin, ...fluoropyrimidines–irinotecan and bevacizumab).
KRAS status was first determined locally but subsequent validation of KRAS status and additional screenings (rare KRAS, NRAS, BRAF mutations and EGFR copy number) were centrally assessed. Patients received panitumumab (6 mg/kg) and irinotecan (180 mg/m²) every 2 weeks.
Sixty-five eligible patients were analyzed. The objective response rate (ORR) was 29.2% 95% confidence interval (95% CI) 18.2–40.3. Median progression-free and overall survivals were 5.5 and 9.7 months, respectively. Most frequent grade 3/4 toxic effects were skin 32.3%, diarrhea 15.4% and neutropenia 12.3%. Tissue samples were available for 60 patients. For the confirmed KRAS wild-type population codon 12 or 13 mutation (n = 54), ORR was 35.2% (95% CI 22.4.1–47.9). Thirteen patients had a NRAS, a BRAF or a rare KRAS mutation, and no tumor response was observed in this subgroup when compared with 46.3% (95% CI 31.1–61.6) ORR in the subgroup of 41 patients with no identified mutation.
Panitumumab and irinotecan is an active third-line regimen in a well-defined population based on biomarkers.
NCT00655499.
Background
First-line treatment with FOLFIRINOX significantly increases overall survival (OS) in patients with metastatic pancreatic adenocarcinoma (PA) compared with gemcitabine. The aim of this ...observational cohort was to evaluate the tolerability and efficacy of this regimen in unresectable locally advanced PA (LAPA).
Patients and Methods
From February 2010 to February 2012, all consecutive patients from 11 French centers treated by FOLFIRINOX for a histologically proven LAPA were prospectively enrolled. Unresectability was defined independently by each center’s multidisciplinary staff at diagnosis. Absence of metastatic disease was confirmed by chest-abdomen-pelvis computed tomography scan. FOLFIRINOX was delivered every 2 weeks as previously reported until progressive disease, major toxicity, or consolidation treatment by radiotherapy and/or surgery.
Results
Seventy-seven patients were enrolled. They received a median number of five cycles (1–30). Grade 3–4 toxicities were neutropenia (11 %), nausea (9 %), diarrhea (6 %), fatigue (6 %), and anemia (1 %). Grade 2–3 sensory neuropathy occurred in 25 % of patients. No toxic death was reported and only 6 % of patients had to stop treatment because of toxicity. Disease control rate was 84 with 28 % of objective response (Response Evaluation Criteria in Solid Tumors). Seventy-five percent of patients received a consolidation therapy: 70 % had radiotherapy and 36 % underwent a surgical resection, with a curative intent. Within the whole cohort, 1-year OS rate was 77 % (95 % CI 65–86) and 1-year progression-free survival rate was 59 % (95 % CI 46–70).
Conclusion
First-line FOLFIRINOX for LAPA seems to be effective and have a manageable toxicity profile. These promising results will have to be confirmed in a phase III randomized trial.
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